This invention relates to a compressed tablet formulation for efavirenz, which is 50 percent by weight drug loaded and can optionally be film coated. Efavirenz is a non-nucleoside reverse trancriptase inhibitor being studied clinically for use in the treatment of HIV infections and AIDS. A process for the manufacture of the compressed tablet is also disclosed.
The synthesis of efavirenz and structurally similar reverse transcriptase inhibitors are disclosed in U.S. Pat. Nos. 5,519,021, 5,663,169, 5,665,720 and the corresponding PCT International Patent Application WO 95/20389, which published on Aug. 3, 1995. Additionally, the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition and cyclization sequence has been described by Thompson, et al., Tetrahedron Letters 1995, 36, 8937–8940, as well as the PCT publication, WO 96/37457, which published on Nov. 28, 1996.
Additionally, several applications have been filed which disclose various aspects of the synthesis of (−)6-chloro-4-cyclopropyl-ethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one including: 1) a process for making the chiral alcohol, U.S. Ser. No. 60/035,462, filed Jan. 14, 1997; 2) the chiral additive, U.S. Ser. No. 60/034,926, filed Jan. 10, 1997; 3) the cyclization reaction, U.S. Ser. No. 60/037,059, filed Feb. 12, 1997; and the anti-solvent crystallization procedure, U.S. Ser. No. 60/037,385 filed Feb. 5, 1997 and U.S. Ser. No. 60/042,807 filed Apr. 8, 1997.
The compressed tablet is an improved formulation which allows one to utilize a tablet over a capsule. The compressed tablet has been demonstrated to have comparable bioavailability data to that seen with the capsule. The key feature of the formulation is the use of a superdisintegrant and disintegrant intragranularly to achieved a bioequivalent formulation. The compressed tablet form was difficult to manage as efavirenz is fragile and the drug loses crystallinity upon compression. This was overcome by adding lactose extragranularly.